Project Abstract Many diverse neural disorders, including bipolar disorder, schizophrenia, post traumatic stress disorder, and conduct disorder, as well as certain types of cortical trauma can result in increased aggression. These effects can be severely compounded when paired with substance abuse. These behavioral effects can take the form of increased ?proactive? aggression-seeking behavior, increased ?reactive? aggressive action, or both. Many of these effects are believed to result from ?top-down? disinhibition of aggression-relevant circuitry, though there is little direct circuit-level or physiological evidence to support this. The goal of this project is to understand and dissociate the precise circuit roles of sources local and long-range inhibition to a hypothalamic neural locus with a clearly identified role in both proactive and reactive aggression. This will potentially lead to a broad new understanding of how activity within these circuits is shaped and gated by inhibition, and how these processes may go awry during social dysfunction. Furthermore, it will provide a much needed circuit-level framework to understand how such diverse disorders can result in similar aggressive phenotypes and may suggests specific circuit components as potential therapeutic targets. While decades of research have implicated the hypothalamus in the generation of ?reactive? aggression, its role in aggression seeking or ?proactive? aggression has been previously unclear. The candidate?s recent work has characterized a new and surprising role for a hypothalamic subdomain, the ventromedial hypothalamus, ventrolateral area, VMHvl, in proactive aggression seeking in addition to its known role in attack. Neurons in this area are active during aggression seeking, and stimulation of this area promotes both aggression seeking and future attack. This area receives direct intra-hypothalamic inhibition as well as inhibition from a number of upstream structures in the amygdala and forebrain, whose roles during proactive and reactive aggression may be dissociable. Newly developed techniques for cell-type specific imaging of deep neural structures now, for the first time, allow interrogation of individual circuit components and can also be used to detect real-time changes in inhibition. This proposal leverages the power of mouse genetics in tandem with new strategies for optical recording, chloride FRET sensing, and cell type specific functional manipulation (Aim 1) to elucidate the roles of VMHvl excitatory and inhibitory subpopulations during aggression seeking and aggression action. In the independent phase of this project, the candidate will expand the scope to map the regulatory roles of sources of long-range inhibition onto the VMHvl and model their effects on the output of aggression- relevant neurons (Aim 2). This will provide a full model how individual neurons become selective for social seeking or action and will also point to neural pathways that could be potential points of intervention during social dysfunction. While this project is focused on aggression-seeking behavior in male mice, these tools can be broadly harnessed for future research on other social seeking behaviors in both females and males. This project brings together an experienced group of mentors and collaborators who will provide critical training for the candidate?s short-term and long-term success, including expertise in genetic targeting strategies, optical recording, functional manipulation, and in vivo ?optrode? recording. The proposed training program combines technical training and formal mentorship alongside the development of professional skills. The goals outlined in this proposal build upon the candidate?s background as primate physiologist and will equip the candidate to successfully transition to leading a laboratory focused on understanding the neural circuitry underlying social motivation.